N-(dialkylaminoalkyl)adamantanecarboxamides and related compounds



United States Patent 3,374,244 N-(DIALKYLAMHNOALKYDADAMANTANECAR-EOXAMIDES AND RELATED CQMPOUNBS Cari Peter Krimrnel, Wauconda, ilL,assignor to G. D. Searle & Co., Chicago, 111., a corporation of DelawareNo Drawing. Continuation-impart of application Ser. N 0.

466,832, June 24, 1965. This application June 3%, 1966, Ser. No.561,7tl7 Claims priority, application Great Britain, June 13, 1966,26,187/66 7 (Iiairns. (Ci. 260-3263) ABSTRACT UP THE DKSQLGSURE Thepresent N-(dialkylaminoallryl)adamantanecarboxamides and relatedcompounds possess anti-inflammatory, antibacterial, anti-protozoal,anti-fungal, and anti-algal activity. The compounds are prepared by thereaction of adamantane-l-carbonyl chloride or the correspondinghomoadamantane compound with a dialkylaminoalkylamine or similarcompound.

The present application is a continuation-in-part of application Ser.No. 466,832, filed June 24, 1965, and now abandoned.

The present invention relates to a group of amides ofadamantanecarboxylic acid and homoadamantanecarboxylic acid. Moreparticularly, it relates to a group of compounds having the followinggeneral formula wherein Ad is selected from the group consisting ofadamantyl and homoadamantyl with, in each case, the free 'valenceoccunng at a bridgehead position; Alk is alkylene separating thenitrogens attached thereto by at least 2 carbon atoms; -NRR is selectedfrom the group consisting of di(lower alkyl)arnino and cyclic amino.Examples of cyclic amino radicals are l-pyrrolidinyl, piperidino,hexamethylenimino, morpholino, and 4-methyl-l-piperazinyl.

The lower alkylene radicals referred to above contain up to 7 carbonatoms and can be exemplified by ethylene, propylene, trimethylene,tetramethylene, pentamethylene, and heptamethylene. The lower .alkylradicals referred to above contain up to 6 carbon atoms and can beexemplified by methyl, ethyl, propyl, isopropyl, butyl, and the like.

The organic bases of this invention form pharmaceutically aceptablesalts with a variety of organic and inorganic acids. Such salts areformed with acids such as sulfuric, phosphoric, hydrochloric,hydrobromic, hydriodic, sulfamic, citric, lactic, maleic, malic,succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic, andrelated acids. They also form quaternary ammonium salts with a varietyof organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids.Among such esters are methyl chloride and bromide, ethyl chloride,propyl chloride, butyl chloride, isobutyl chloride, benzyl chloride andbromide, phenethyl bromide, naphthylmethyl chloride, dimethyl sulfate,methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin,propylene chlorohydrin, allyl bromide, methallyl bromide, and crotylbromide.

The compounds of this invention are conveniently prepared from thereaction of an amine of the formula H NAlkNRR', wherein Alk and NRR' aredefined as above, with an adamantane or homoadamantane carboxylic acidhalide. The acid chloride is preferred for this reaction. The reactionis carried out in an inert sol- 3,374,244 Patented Mar. 19, 1968 ventsuch as benzene or a tertiary amine such as pyridine. In some instances,it may be necessary to apply external heat to the mixture in order formore complete reaction to take place.

The compounds of the invention are useful because of theirpharmacological properties. In particular, these compounds possessanti-inflammatory activity. Thus, they have a phenylb-utazone-likeeifect on edematous conditions. In addition, they possess antibioticactivity against a variety of organisms. Thus, they inhibt the growth ofbacteria such as Diplococcus pneumoniae, protozoa such as Tetrahymenagelleii, fungi such as Trichophyton mentagrophytes and Candida albicans,and algae such as Chlorella vulgaris. They also inhibit germination ofseeds of Trifolium.

The following examples are presented to further illustrate the presentinvention; they should not -be construed as limiting it in spirit or inscope. In these examples, quantities by weight are indicated in grams,quantities by volume are indicated in milliliters, and temperatures areindicated in degrees centigrade C.).

Example 1 A mixture of 3.0 grams of adamantane-l-carboxylic acid and 20ml. of thionyl chloride is refluxed for 30 minutes. Unreacted thinoylchloride is then removed by distilling the mixture under reducedpressure on a steam bath. Azeothropically dried benzene is then added tothe residue and distillation is resumed to remove any final traces ofthionyl chloride. After removal of the benzene, the residualadamantane-l-carbonyl chloride is dissolved in 20 ml. of dry benzene and1.7 grams of 3-dimethylaminopropylamine is added portionwise withstirring. The resultant reaction mixture is then allowed to cool for 30minutes during which time 2 layers form. The lower layer solidifies to acrystalline slurry which is separated by filtration, washed withbenzene, and dried. It is then dissolved in 350 ml. of boiling acetoneand the solution is treated with decolorizing charcoal, concentrated,and cooled. The solid which separates is then filtered and dried to giveN-(3-dimethylaminopropyl)adamantane-l-carboxamide hydrochloride meltingat about l57l61 C.

Example 2 To a solution of 5 grams of B-dimethylaminopropylamine in 20ml. of pyridine is added, with stirring and cooling, 4.7 grams ofadamantane-l-carbonyl chloride over a 10 minute period. The resultantreaction mixture is allowed to stand at room temperature for about 16hours and is then poured into 200 ml. of water. The aqueous solution ismade acidic by the addition of 10% hydrochloric acid and then washedwith ethyl acetate. The aqueous layer is made basic by the addition of20% sodium hydroxide solution and extracted with ether and ethylacetate. The extract is then washed twice with Water and dried overanhydrous sodium sulfate. Removal of the solvent by vacuum distillationaffords an oil which solidifies on standing. Recrystallization of thesolid from hexane gives N-(3-dimethylaminopropyl)adamantane-lcarboxamideas crystals melting at about 7778 C. This compound has the followingformula Example 3 Adamantane-l-carbonyl chloride is prepared from 3.0grams of adamantane-l-carboxylic acid according to the proceduredescribed in Example 1. The acid chloride is then dissolved in ml. ofazeotropically dried benzene and, to this solution, there is added withstirring 2.0 grams of 2-diethylaminoethylamine in 10 ml. of driedbenzene. The resultant mixture is then cooled and the solid which formsis separated by filtration and dried. It is then dissolved in 500 ml. ofrefluxing acetone, treated with charcoal, and concentrated. The whitecrystals which form in the cooled concentrated solution are separated byfiltration to give N-(2-diethylaminoethyl)adamantane-1- carboxamidehydrochloride melting at about 190-193 C.

2.0 grams of this amide is dissolved in 30 ml. of water and the solutionis made alkaline by the addition of 3.0 grams of sodium hydroxide in ml.of water. The mixture is then extracted with ether and the ether extractis separated and dried. Evaporation of the solvent from ether thesolution gives a pale yellow oil which solidifies on cooling to give afriable crystalline mass melting at about 7680 C. This product isN-(2-diethylaminoethyl)adamantane-l-carboxamide and it has the followingformula CHzCH;

CHzCH;

Example 4 Example 5 Adaniantane-l-carbonyl chloride is prepared from 8.0grams of adamantane-l-carboxylic acid according to the proceduredescribed in Example 1. The acid chloride is then dissolved in 50 ml. ofanhydrous benzene and to this solution is added, with stirring, 3.9grams of 2-dimethylaminoethylamine in 50 ml. of anhydrous benzene. Thewhite precipitate which forms after standing for a period of 2 hours isseparated by filtration and dried. The resultant crude product is thendissolved in 700 ml. of hot Z-butanone, treated with decolorizingcharcoal, and filtered hot through diatomaceous earth. Concentration andcooling of the filtrate givesN-(Z-dimethylaminoethyl)adamantane-l-carboxamide hydrochloride as white,needle-like crystals melting at about 206-209 C.

Example 6 Homoadamantane-3-carbonyl chloride is prepared from 3.0 gramsof homoadamantane-3-carboxylic acid according to the procedure describedin Example 1 for the preparation of adamantane-l-carbonyl chloride. Theacid chloride is then dissolved in 10 ml. of anhydrous pyridine and, tothis solution, there is added 1.9 grams of Z-diethylaminoethylamine in10 ml. of anhydrous pyridine. The resultant mixture is heated on a steambath for about one hour and then cooled. The solid which forms isseparated by filtration, washed with 10 ml. of anhydrous benzene, anddried. It is then dissolved in refluxing Z-butanone, treated withdecolorizing charcoal, and filtered through diatomaceous earth. Theresultant filtrate is cooled to giveN-(Z-diethylaminoethyl)homoadamantane-B-carboxamide hydrochloride,melting at about 195- 198 C. The free base of this compound has thefollowing formula Example 7 Example 8 Adamantane-l-carbonyl chloride isprepared from 8.0 grams of adamantane-l-carboxylic acid according to theprocedure described in Example 1. The acid chloride is then dissolved in50 ml. of anhydrous benzene and to this solution there is added, withstirring, 8.5 grams of N,N- diethyl-1,7-heptanediamine in 50 ml. ofanhydrous benzene. The resultant mixture gives, upon cooling, standingat room temperature and scratching, a white granular crystallineprecipitate which is separated by filtration and dried. This crudeproduct is dissolved in 700 ml. of hot Z-butanone, treated withcharcoal, and then filtered through diatomaceous earth. The resultantfiltrate is concentrated and cooled and then allowed to stand at roomtemperature for about 6 hours. This givesN-(7-diethylaminoheptyl)adamantane-1 carboxamide hydrochloride, meltingat about l30l41 C.

The necessary diamine starting material is obtained by the followingprocedure. 220 grams of hexamethylene chlorohydrin is reacted with 221grams of phosphorus tribromide according to the procedure described byCloke et al., J. Am. Chem. Soc. 53, 2791 (1931), to give hexamethylenechlorobromide boiling at about 9294 C. at 9.0 mm. pressure. 286 grams ofthe chlorobromide is reacted with 112 grams of potassium cyanideaccording to the procedure described in A. H. Blatt Organic Syntheses,coll. vol. I, John Wiley & Sons, Inc., New York, N.Y., 1941, page 156 togive 7-chloroheptanonitrile boiling at about 12l124 C. at 8.0 pressure.

A mixture of grams of the above chloronitrile, grams of diethylamine and2 grams of potassium iodide in 150 ml. of 2-butanone is placed in 2pressure bottles and heated in a steam cabinet for 90 hours. Theresultant mixtures are cooled and filtered and the solvent is evaporatedfrom the combined filtrate. The residue is made acid with dilutehydrochloric acid and washed once with ether, and the acid solution isthen made alkaline with 40% sodium hydroxide solution. The alkalinesolution is then saturated with solid potassium carbonate and an oil issalted out. The resultant mixture is extracted with ether and the etherextract is dried over sodium sulfate and the solvent is evaporated. Theresidue is then distilled to give 7-diethylaminoheptanonitrile boilingat about 128- l3l C. at 7.0 mm. pressure. A solution of 102 grams of the7-diethylaminoheptanonitrile and 44 grams of ammonia in 500 ml. ofmethanol is hydrogenated over Raney nickel at a pressure of about 680pounds and a temperature of about 49 C. The mixture is then cooled andfiltered and the residue is distilled to giveN,N-diethyl-1,7-heptanediamine boiling at about 109-110.5 C. at 6 mm.pressure.

Example 9 Adamantane-l-carbonyl chloride is prepared from 8.0 grams ofadamantane-l-carboxylic acid according to the procedure described inExample 1. The acid chloride is dissolved in 50 ml. of anhydrous benzeneand, to this solution, there is added with stirring 5.8 grams of 1-(2-aminoethyl)piperidine in 50 ml. of anhydrous benzene. The resultantbrown solution is then cooled and the solid which forms is separated byfiltration and dried. It is dissolved in 700 ml. of refluxing2-butanone, treated with decolorizing carbon, and filtered hot throughdiatomaceous earth. The filtrate is cooled to giveN-(Z-piperidinoethyl)adamantane-l-carboxarnide hydrochloride, melting atabout 19820l C.

Example To 7.3 grams of adamantane-l-carbonyl chloride in 175 ml. ofanhydrous benzene is added 5.2 grams of 1-(3- aminopropyDpiperidine. Theresulting solution is refluxed, with stirring, for a period of about onehour, after which time it is allowed to stand at room temperature forabout 64 hours. The solution is then stirred and cooled in ice. Theprecipitate which for-ms is collected by filtration, washed with etherand dried in vacuo. A portion of the resulting crude product isrecrystallized from acetone to yieldN-(3-piperidinopropyl)adamantane-l-carboxamicle hydrochloride, meltingat about 171-174 C.

The remaining portion of the crude product is dissolved in Water andtreated with a 5% sodium carbonate solution. The oil which formsgradually solidifies, and is collected by filtration and dried to yieldN-(3-pi-peridinopropyl) adamantanel-carboxamide.

Example 11 Adamantane-l-carbonyl chloride is prepared from 3.0 grams ofadaman-tane-l-carboxylic acid according to the procedure described inExample 1. The acid chloride is then dissolved in ml. of anhydrousbenzene and the resultant solution is added, at one time and withstirring, to a solution of 2.2 grams of 1-(3-aminopropyl)pyrrolidine in20 ml. of anhydrous benzene. The resultant reaction mixture is refluxedfor minutes before it is cooled and extracted with 200 ml. of water. Theaqueous extract is filtered through decolorizing charcoal and theresultant filtrate is made alkaline by the addition of 10% sodiumhydroxide solution. An oil separates and the resultant mixture isextracted with ether. The ether extract is treated with decolorizingcarbon and dried over anhydrous calcium sulfate. The ether solvent isthen removed and the residue is seeded with a crystal of thediethylaminoethyl compound of Example 3. The product thus obtained as apale yellow powder isN-[3-(l-pyrrolidinyl)propyl]adamantane-l-carboxamide and it melts atabout 6569 C.

Similarly, adamantane-l-carbonyl chloride is reacted with4-(2-aminoethyl)rnorpholine and with I-(Z-aminoethyDheXameth-yleneimineaccording to the procedure detailed above to give, respectively,N-(Z-morpholinoethyl) adamantane-l-carboxamide and N(Z-hexamethyleneiminoethyl) adamantane-l-carboxamide.

Example 12 To a solution of 5 grams of adamantane-l-carbonyl chloride in125 ml. of benzene is added 3 grams of l- (Z-aminoethyl)pyrrolidine. Thereaction mixture is heated at reflux for about one-half hour, and thenallowed to stand at room temperature for about 16 hours. The precipitatewhich forms is separated by filtration and recrystallized from asolution containing acetone combined with methanol and water to giveN-[Z-(I-pyrrolidinyl) ethyl]adamantane-l-carboxamide hydrochloride,melting at about 225226 C.

6 Example 13 To a solution of 4 grams of 1-(3-aminopropyl)-4-methylpiperazine in 20 ml. of pyridine is added, with stirring andcooling, 5 grams of adamantane-l-carbonyl chloride over a period of 10minutes. The resultant reaction mixture is allowed to stand at roomtemperature for about 40 hours and then is poured into ml. of water. Thesolid which forms is separated by filtration and identified asadamantane-l-carboxylic acid. The filtrate is made acidic by theaddition of 10% hydrochloric acid. The non-aqueous layer is extractedwith ethyl acetate and discarded. The remaining aqueous layer is madebasic by the addition of sodium carbonate and then extracted with ethylacetate, Washed three times with water and dried over anhydrous sodiumsulfate. Removal of the solvent by distillation gives an oil whichsolidifies to 3ield N- 3-(4-methyl-l-piperazinyl)propyl]adamantanel-carboxamide.

0.8 gram of the above product is dissolved in ether and treated withisopropanolic hydrogen chloride. The product obtained is collected byfiltration and recrystallized from ethanol-acetone to give thedihydro-chlori-de salt of the product of the preceding paragraph. Thissalt decomposes at about 210 C. The free base has the following formulaN-CHa (llHa What is claimed is:

1. A member selected from the group consisting of compounds of theformula lNH-AlkN (lower alkyl) 1 wherein Alk is alkylene having from 2to 7 carbon atoms and separating the nitrogens attached thereto by atleast 2 carbon atoms.

3. A compound according to claim 1 which has the formula wherein Alli isalkylenc having from 2 to 7 carbon atoms and separating the nitrogensattached thereto by at least 2 carbon atoms.

4. A compound according to claim 1 which is N-(2- dicthylaminocthyl)adamantane-l-carboxamide.

5. A compound according to claim 1 which is N-(3- dimethyiaminopropyl)adamantancl-carboxamide.

6. A compound according to claim 1 which is N-[3-(1- pyrrolidinylpropyl] adamantanel-carboxamide.

7. A compound according to claim 1 which is N-(Z-diethylamincethyl)homoadamantane-3-carboxamide.

8 References Cited FOREIGN PATENTS 1,353,906 8/1964 France.

ALEX, MAZEL, Primary Examiner.

J. TOVAR, Assistant Examiner.

Patent No. 3,374,244

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION March 19, 1968Carl Peter Krimmel It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereby corrected asshown below:

Column 3, line 20, "ether the" should read the ether Column 4, theformula should appear as shown below:

Signed and sealed this 2nd day of December 1969.

(SEAL) Attest:

Edward M. Fletcher, Jr.

Attesting Officer Commissioner of Patents WILLIAM E. SCHUYLER, JR.

